GlcNAc 2-epimerase can serve a catabolic role in sialic acid metabolism
GlcNAc 2-epimerase can serve a catabolic role in sialic acid metabolism
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DOI：
10.1074/jbc.m212127200
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发表时间：
2003-03-07
影响因子：
4.8
通讯作者：
Bertozzi, CR
中科院分区：
文献类型：
--
作者：
Luchansky, SJ;Yarema, KJ;Bertozzi, CR
唾液酸是与人类健康和疾病相关的许多系统中碳水化合物-受体相互作用的主要决定因素。n -乙酰甘露糖胺（ManNAc）是唾液酸生物合成途径中第一个稳定的中间体；因此，控制胞内甘露聚糖水平的机制是唾液酸产生的重要调节因子。UDP-GlcNAc 2-epimerase和GlcNAc 2-epimerase是两种能够分别从UDP-GlcNAc和GlcNAc生成甘露聚糖的酶。虽然前一种酶已被证明在体内将代谢通量导向唾液酸，但后一种酶的功能尚不清楚。本文研究GlcNAc 2- epimase表达对细胞唾液酸生成的影响。我们为这项研究开发的一个关键工具是基于机制原理设计的细胞渗透性小分子GlcNAc 2- epimase抑制剂。我们的研究结果表明，与UDPGlcNAc 2- epimase促进唾液酸的生物合成不同，GlcNAc 2- epimase可以发挥分解代谢作用，将代谢通量从唾液酸途径转移。
Sialic acid is a major determinant of carbohydrate-receptor interactions in many systems pertinent to human health and disease. N-Acetylmannosamine (ManNAc) is the first committed intermediate in the sialic acid biosynthetic pathway; thus, the mechanisms that control intracellular ManNAc levels are important regulators of sialic acid production. UDP-GlcNAc 2-epimerase and GlcNAc 2-epimerase are two enzymes capable of generating ManNAc from UDP-GlcNAc and GlcNAc, respectively. Whereas the former enzyme has been shown to direct metabolic flux toward sialic acid in vivo, the function of the latter enzyme is unclear. Here we study the effects of GlcNAc 2-epimerase expression on sialic acid production in cells. A key tool we developed for this study is a cell-permeable, small molecule inhibitor of GlcNAc 2-epimerase designed based on mechanistic principles. Our results indicate that, unlike UDPGlcNAc 2-epimerase, which promotes biosynthesis of sialic acid, GlcNAc 2-epimerase can serve a catabolic role, diverting metabolic flux away from the sialic acid pathway.